4-amino-azepan-3-one compounds as cathepsin k inhibitors useful in the treatment of osteoporosis

ABSTRACT

This invention relates to compounds of formula (I) which are cysteine protease inhibitors, in particular, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

BACKGROUND OF THE INVENTION

A variety of disorders in humans and other mammals involve or areassociated with abnormal bone resorption. Such disorders include, butare not limited to, osteoporosis, glucocorticoid induced osteoporosis,Paget's disease, abnormally increased bone turnover, periodontaldisease, tooth loss, bone fractures, rheumatoid arthritis,osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta,metastatic bone disease, hypercalcemia of malignancy, and multiplemyeloma. One of the most common of these disorders is osteoporosis,which in its most frequent manifestation occurs in postmenopausal women.Osteoporosis is a systemic skeletal disease characterized by a low bonemass and microarchitectural deterioration of bone tissue, with aconsequent increase in bone fragility and susceptibility to fracture.Osteoporotic fractures are a major cause of morbidity and mortality inthe elderly population. As many as 50% of women and a third of men willexperience an osteoporotic fracture. A large segment of the olderpopulation already has low bone density and a high risk of fractures.There is a significant need to both prevent and treat osteoporosis andother conditions associated with bone resorption. Because osteoporosis,as well as other disorders associated with bone loss, are generallychronic conditions, it is believed that appropriate therapy willtypically require chronic treatment.

Osteoporosis is characterized by progressive loss of bone architectureand mineralization leading to the loss in bone strength and an increasedfracture rate. The skeleton is constantly being remodeled by a balancebetween osteoblasts that lay down new bone and osteoclasts thatbreakdown, or resorb, bone. In some disease conditions and advancing agethe balance between bone formation and resorption is disrupted; bone isremoved at a faster rate. Such a prolonged imbalance of resorption overformation leads to weaker bone structure and a higher risk of fractures.

Bone resorption is primarily performed by osteoclasts, which aremultinuclear giant cells. Osteoclasts resorb bone by forming an initialcellular attachment to bone tissue, followed by the formation of anextracellular compartment or lacunae. The lacunae are maintained at alow pH by a proton-ATP pump. The acidified environment in the lacunaeallows for initial demineralization of bone followed by the degradationof bone proteins or collagen by proteases such as cysteine proteases.See Delaisse, J. M. et al., 1980, Biochem J 192:365-368; Delaisse, J. etal., 1984, Biochem Biophys Res Commun: 441-447; Delaisse, J. M. et al.,1987, Bone 8:305-313, which are hereby incorporated by reference intheir entirety. Collagen constitutes 95% of the organic matrix of bone.Therefore, proteases involved in collagen degradation are an essentialcomponent of bone turnover, and as a consequence, the development andprogression of osteoporosis.

Cathepsins belong to the papain superfamily of cysteine proteases. Theseproteases function in the normal physiological as well as pathologicaldegradation of connective tissue. Cathepsins play a major role inintracellular protein degradation and turnover and remodeling. To date,a number of cathepsin have been identified and sequenced from a numberof sources. These cathepsins are naturally found in a wide variety oftissues. For example, cathepsin B, F, H, L, K, S, W, and Z have beencloned. Cathepsin K (which is also known by the abbreviation cat K) isalso known as cathepsin O and cathepsin O2. See PCT Application WO96/13523, Khepri Pharmaceuticals, Inc., published May 9, 1996, which ishereby incorporated by reference in its entirety. Cathepsin L isimplicated in normal lysosomal proteolysis as well as several diseasesstates, including, but not limited to, metastasis of melanomas.Cathepsin S is implicated in Alzheimer's disease and certain autoimmunedisorders, including, but not limited to juvenile onset diabetes,multiple sclerosis, pemphigus vulgaris, Graves' disease, myastheniagravis, systemic lupus erythemotasus, rheumatoid arthritis andHashimoto's thyroiditis; allergic disorders, including, but not limitedto asthma; and allogenic immunbe responses, including, but not limitedto, rejection of organ transplants or tissue grafts. Increased CathepsinB levels and redistribution of the enzyme are found in tumors,suggesting a role in tumor invasion and matastasis. In addition,aberrant Cathpsin B activity is implicated in such disease states asrheumatoid arthritis, osteoarthritis, pneumocystisis carinii, acutepancreatitis, inflammatory airway disease and bone and joint disorders.

Cysteine protease inhibitors such as E-64(trans-epoxysuccinyl-L-leucylamide-(4-guanidino)butane) are known to beeffective in inhibiting bone resorption. See Delaisse, J. M. et al.,1987, Bone 8:305-313, which is hereby incorporated by reference in itsentirety. Recently, cathepsin K was cloned and found specificallyexpressed in osteoclasts See Tezuka, K. et al., 1994, J Biol Chem269:1106-1109; Shi, G. P. et al., 1995, FEBS Lett 357:129-134; Bromme,D. and Okamoto, K., 1995, Biol Chem Hoppe Seyler 376:379-384; Bromme, D.et al., 1996, J Biol Chem 271:2126-2132; Drake, F. H. et al., 1996, JBiol Chem 271:12511-12516, which are hereby incorporated by reference intheir entirety. Concurrent to the cloning, the autosomal recessivedisorder, pycnodysostosis, characterized by an osteopetrotic phenotypewith a decrease in bone resorption, was mapped to mutations present inthe cathepsin K gene. To date, all mutations identified in the cathepsinK gene are known to result in inactive protein. See Gelb, B. D. et al.,1996, Science 273:1236-1238; Johnson, M. R. et al., 1996, Genome Res6:1050-1055, which are hereby incorporated by reference in theirentirety. Therefore, it appears that cathepsin K is involved inosteoclast mediated bone resorption.

Cathepsin K is synthesized as a 37 kDa pre-pro enzyme, which islocalized to the lysosomal compartment and where it is presumablyautoactivated to the mature 27 kDa enzyme at low pH. See McQueney, M. S.et al., 1997, J Biol Chem 272:13955-13960; littlewood-Evans, A. et al.,1997, Bone 20:81-86, which are hereby incorporated by reference in theirentirety. Cathepsin K is most closely related to cathepsin S having 56%sequence identity at the amino acid level. The S₂P₂ substratespecificity of cathepsin K is similar to that of cathepsin S with apreference in the P1 and P2 positions for a positively charged residuesuch as arginine, and a hydrophobic residue such as phenylalanine orleucine, respectively. See Bromme, D. et al., 1996, J Biol Chem 271:2126-2132; Bossard, M. J. et al., 1996, J Biol Chem 271:12517-12524,which are hereby incorporated by reference in their entirety. CathepsinK is active at a broad pH range with significant activity between pH4-8, thus allowing for good catalytic activity in the resorption lacunaeof osteoclasts where the pH is about 4-5.

Human type I collagen, the major collagen in bone is a good substratefor cathepsin K. See Kafienah, W., et al., 1998, Biochem J 331:727-732,which is hereby incorporated by reference in its entirety. In vitroexperiments using antisense oligonucleotides to cathepsin K, have showndiminished bone resorption in vitro, which is probably due to areduction in translation of cathepsin K mRNA. See Inui, T., et al.,1997, J Biol Chem 272:8109-8112, which is hereby incorporated byreference in its entirety. The crystal structure of cathepsin K has beenresolved. See McGrath, M. E., et al., 1997, Nat Struct Biol 4:105-109;Zhao, B., et al., 1997, Nat Struct Biol 4: 109-11, which are herebyincorporated by reference in their entirety. Also, selective peptidebased inhibitors of cathepsin K have been developed See Bromme, D., etal., 1996, Biochem J 315:85-89; Thompson, S. K., et al., 1997, Proc NatlAcad Sci USA 94:14249-14254, which are hereby incorporated by referencein their entirety. Accordingly, inhibitors of Cathepsin K can reducebone resorption. Such inhibitors would be useful in treating disordersinvolving bone resorption, such as osteoporosis.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are capable of treatingand/or preventing cathepsin dependent conditions or disease states in amammal in need thereof. One embodiment of the present invention isillustrated by a compound of Formula I, and the pharmaceuticallyacceptable salts, stereoisomers and N-oxide derivatives thereof:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the following chemicalformula:

wherein R¹ is hydrogen, C₁₋₆ alkyl, —SO₂R⁹, —C(O)R⁹ or arylC₁₋₆alkyl;

-   R² is hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl;-   R³ is hydrogen, C₁₋₆ alkyl or C₂₋₆ alkenyl wherein said alkyl and    alkenyl groups are optionally substituted with C₃₋₆ cycloalkyl or    halo;-   R⁴ is hydrogen, C₁₋₆ alkyl or C₂₋₆ alkenyl wherein said alkyl and    alkenyl groups are optionally substituted with C₃₋₆ cycloalkyl or    halo;-   or R³ and R⁴ can be taken together with the carbon atom to which    they are attached to form a C₃₋₈ cycloalkyl ring, C₅₋₈ cycloalkenyl    ring, or five to seven membered heterocyclyl wherein said    cycloalkyl, cycloalkenyl and heterocyclyl groups are optionally    substituted with C₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or    keto;-   R⁵ is selected from hydrogen or C₁₋₆ alkyl substituted with 1-6    halo;-   R⁶ is aryl, heteroaryl, C₁₋₆ haloalkyl, arylalkyl or    heteroarylalkyl, wherein said aryl, heteroaryl, arylalkyl and    heteroarylalkyl groups are optionally substituted with halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, —SR⁹, —SR¹², —SOR⁹, —SOR¹²,    —SO₂R⁹, —SO₂R^(12,) —SO₂CH(R¹²)(R¹¹), —OR¹², —N(R¹⁰)(R¹¹) or cyano;-   D is C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, aryl, heteroaryl, C₃₋₈    cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl    and heterocyclyl groups, which may be monocyclic or bicyclic, are    optionally substituted on either the carbon or the heteroatom with    one to five substituents selected from C₁₋₆ alkyl, halo or keto;-   R⁷ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkyloxy, halo, nitro, cyano, aryl, heteroaryl, C₃₋₈ cycloalkyl,    heterocyclyl, —C(O)OR¹⁰, —C(O)OSi[CH(CH₃)₂]₃, —OR¹⁰, —C(O)R¹⁰,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)N(R¹²)(R¹²), —C(O)N(R¹⁰)(R¹¹),    —C(R¹⁰)(R¹¹)OH, —SR¹², —SR⁹, —R¹⁰SR⁹, —R⁹, —C(R⁹)₃,    —C(R¹⁰)(R¹¹)N(R⁹)₂, —NR¹⁰C(O)NR¹⁰S(O)₂R⁹, —SO₂R¹², —SO(R¹²), —SO₂R⁹,    —SO₂N(R^(c))(R^(d)), —SO₂CH(R¹⁰)(R¹¹), —SO₂N(R¹⁰)C(O)(R¹²),    —SO₂(R¹⁰)C(O)N(R¹²)₂, —OSO₂R¹⁰, —N(R¹⁰)(R¹¹), —N(R¹⁰)C(O)N(R¹⁰)(R⁹),    —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)SO₂(R¹⁰),    —C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R⁹, —C(R¹⁰)(R¹¹)N(R¹⁰)R⁹,    —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)R⁹, R¹⁰S—,    —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b))₂,    —C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R⁹,    —C(O)C(R^(a))(R^(b))S(R^(a))(R^(b)) or    C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said groups are    optionally substituted on either the carbon or the heteroatom with    one to five substituents independently selected from C₁₋₆ alkyl,    halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR⁹, —O(aryl), —NO₂,    —NH₂, —NHS(O)₂R⁸, —R⁹SO₂R¹², SO₂R¹², SO(R¹²), SO₂N(R^(c))(R^(d)),    SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —COOH,    —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹),    —NH(CH₂)₂OH, —NHC(O)OR¹⁰, Si(CH₃)₃, heterocycyl, aryl or heteroaryl;-   R⁸ is hydrogen or C₁₋₆ alkyl;-   or R⁴ and R⁸ or can be taken together with any of the atoms to which    they may be attached or are between them to form a 4-10 membered    heterocyclyl ring system wherein said ring system, which may be    monocyclic or bicyclic, is optionally substituted with C₁₋₆ alkyl,    halo, hydroxyalkyl, hydroxy, keto, OR¹⁰, SR¹⁰ or N(R¹⁰)₂;-   R⁹ is selected from the group consisting of hydrogen, aryl,    aryl(C₁₋₄) alkyl, heteroaryl, heteroaryl(C₁₋₄)alkyl, C₃₋₈cycloalkyl,    C₃₋₈cycloalkyl(C₁₋₄)alkyl, and heterocyclyl(C₁₋₄)alkyl wherein said    groups can be optionally substituted with halo or alkoxy;-   R¹⁰ is hydrogen or C₁₋₆ alkyl;-   R¹¹ is hydrogen or C₁₋₆ alkyl;-   R¹² is hydrogen or C₁₋₆ alkyl which is optionally substituted with    halo, alkoxy, cyano, —NR¹⁰ or —SR¹⁰;-   R^(a) is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆    alkyl)hydroxyl, —O(C₁₋₆ alkyl), hydroxyl, halo, aryl, heteroaryl,    C₃₋₈ cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl,    C₃₋₈ cycloalkyl and heterocyclyl can be optionally substituted on    either the carbon or the heteroatom with C₁₋₆ alkyl or halo;-   R^(b) is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl,    (C₁₋₆alkyl)hydroxyl, alkoxyl, hydroxyl, halo, aryl, heteroaryl, C₃₋₈    cycloalkyl, heterocyclyl,wherein said alkyl, aryl, heteroaryl, C₃₋₈    cycloalkyl and heterocyclyl can be optionally substituted on either    the carbon or the heteroatom with C₁₋₆ alkyl or halo;-   or R^(a) and R^(b) can be taken together with the carbon atom to    which they are attached or are between them to form a C₃₋₈    cycloalkyl ring or C₃₋₈ heterocyclyl ring wherein said 3-8 membered    ring system may be optionally substituted with C₁₋₆ alkyl and halo;-   R^(c) is hydrogen or C₁₋₆ alkyl which is optionally substituted with    halo or OR⁹;-   R^(d) is hydrogen or C₁₋₆ alkyl which is optionally substituted with    halo or OR⁹;-   or R^(c) and R^(d) can be taken together with the nitrogen atom to    which they are attached or are between them to form a C₃₋₈    heterocyclyl ring which is optionally substituted with C₁₋₆ alkyl,    halo hydroxyalkyl, hydroxy, alkoxy or keto;-   n is independently selected from an integer from zero to three;-   and the pharmaceutically acceptable salts, stereoisomers and N-oxide    derivatives thereof.

In an embodiment of the invention, R¹ is —SO₂R⁹and R² is hydrogen. In anembodiment of the invention, R³ and R⁴ are each independently C₁₋₄ alkylor H. In a further embodiment of the invention R³ is isobutyl and R⁴ isH. In another embodiment of the invention, R³ and R⁴, when on the samecarbon atom, can be taken together with the carbon atom to which theyare attached to form C₃₋₈ cycloalkyl ring, C₅₋₈ cycloalkenyl ring, orfive to seven membered heterocyclyl wherein said cycloalkyl,cycloalkenyl and heterocyclyl groups are optionally substituted withC₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or keto. Examples ofring systems that can be formed include, but are not limited to thefollowing, keeping in mind that the heterocycle is optionallysubstituted with one or more substituents as described above:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Apreferred embodiment is when cyclohexyl is formed.

In an embodiment of the invention, R⁵ is C₁₋₆ alkyl substituted with 1-6halo and R⁶ is C₁₋₆ alkyl substituted with 1-6 halo. In anotherembodiment of the invention, R⁵ is hydrogen and R⁶ is C₁₋₆ alkylsubstituted with 1-6 halo. In a further embodiment, R⁵ is hydrogen andR⁶ is C₁₋₆ alkyl substituted with 1-6 fluoro. In a further embodiment,R⁵ is hydrogen and R⁶ is C₁₋₃ alkyl substituted with 3 fluoro. Inanother embodiment of the invention, R⁵ is hydrogen and R⁶ is aryl orheteroaryl, wherein said aryl and heteroaryl are optionally substitutedwith halo or —SO₂R¹².

In an embodiment of the invention, R⁴ and R⁸ or can be taken togetherwith any of the atoms to which they may be attached or are between themto form a 4-10 membered heterocyclyl ring system wherein said ringsystem, which may be monocyclic or bicyclic, is optionally substitutedwith C₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, keto, —OR¹⁰, —SR¹⁰ or—N(R¹⁰)₂. In a further embodiment of the invention, R⁴ and R⁸ aredefined such that they can be taken together with the nitrogen to whichthey are attached to form a monocyclic or bicyclic heterocyclyl with 5-7members in each ring and optionally containing, in addition to thenitrogen, 1 or 2 additional heteroatoms selected from N, O and S, saidheterocycle optionally substituted with one or more substituentsselected from C₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, keto, —OR¹⁰,—SR¹⁰ or —N(R¹⁰)₂. Nonlimiting examples of heterocyclyl ring systemsthat can be formed include piperazinyl, piperidinyl, pyrrolidinyl andthe like. In a further example, R⁴ and R⁸ are defined such that they canbe taken together with the nitrogen to which they are attached to form a5 or 6 membered heterocyclyl ring system. Examples of the heterocyclesthat can thus be formed include, but are not limited five or sixmembered rings containing at least one nitrogen, which is optionallysubstituted with one or more substituents as described above. Apreferred embodiment is when optionally substituted pyrolidinyl isformed.

In another embodiment of the invention, R^(a) and R^(b), can be takentogether with the carbon atom to which they are attached or are betweenthem to form a C₃₋₈ cycloalkyl ring or a C₃₋₈ heterocyclyl ring whereinthe cycloalkyl and heterocyclyl systems are optionally substituted withC₁₋₆ alkyl and halo. Examples of ring systems that can be formedinclude, but are not limited to the following, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, imidazolyl, piperazinyl,piperidinyl, pyrrolidinyl and the like.

Embodied by the present invention are methods for treating disordersrelated to abnormal bone resoprtion. Such disorders include, but are notlimited to, osteoporosis, glucocorticoid induced osteoporosis, Paget'sdisease, abnormally increased bone turnover, periodontal disease, toothloss, bone fractures, rheumatoid arthritis, osteoarthritis,periprosthetic osteolysis, osteogenesis imperfecta, metastatic bonedisease, hypercalcemia of malignancy, and multiple myeloma. A preferredembodiment includes methods for treating osteoporosis and metastaticbone disease. A more preferred embodiment includes methods for treatingosteoporosis.

Specific embodiments of the present invention include, but are notlimited to:N¹-[3-Oxo-1-(pyridin-2-ylsulfonyl)azepan-4-yl]-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide,and the pharmaceutically acceptable salts, stereoisomers and N-oxidederivatives thereof.

Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound of Formula Ias described above and a pharmaceutically acceptable carrier. Theinvention is also contemplated to encompass a pharmaceutical compositionwhich is comprised of a pharmaceutically acceptable carrier and any ofthe compounds specifically disclosed in the present application. Theseand other aspects of the invention will be apparent from the teachingscontained herein.

Utilities

The compounds of the present invention are inhibitors of cathepsins andare therefore useful to treat or prevent cathepsin dependent diseases orconditions in mammals, preferably humans. Specifically, the compounds ofthe present invention are inhibitors of Cathepsin K and are thereforeuseful to treat or prevent Cathepsin K dependent diseases or conditionsin mammals, preferably humans.

“Cathepsin dependent diseases or conditions” refers to pathologicconditions that depend on the activity of one or more cathepsins.“Cathepsin K dependent diseases or conditions” refers to pathologicconditions that depend on the activity of Cathepsin K. Diseasesassociated with Cathepsin K activities include osteoporosis,glucocorticoid induced osteoporosis, Paget's disease, abnormallyincreased bone turnover, periodontal disease, tooth loss, bonefractures, rheumatoid arthritis, osteoarthritis, periprostheticosteolysis, osteogenesis imperfecta, metastatic bone disease,hypercalcemia of malignancy, and multiple myeloma. In treating suchconditions with the instantly claimed compounds, the requiredtherapeutic amount will vary according to the specific disease and isreadily ascertainable by those skilled in the art. Although bothtreatment and prevention are contemplated by the scope of the invention,the treatment of these conditions is the preferred use.

An embodiment of the invention is a method of inhibiting cathepsinactivity in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of any of the compounds or anyof the pharmaceutical compositions described above.

A class of the embodiment is the method wherein the cathepsin activityis cathepsin K activity.

Another embodiment of the invention is a method of treating orpreventing cathepsin dependent conditions in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above.

A class of the embodiment is the method wherein the cathepsin activityis cathepsin K activity.

Another embodiment of the invention is a method of inhibiting bone lossin a mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above. Another embodiment of theinvention is a method of reducing bone loss in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above. The utility of cathepsin K inhibitors in the inhibitionof bone resorption is known in the literature, see Stroup, G. B., Lark,M. W., Veber, D F., Bhattacharrya, A., Blake, S., Dare, L. C., Erhard,K. F., Hoffman, S. J., James, I. E., Marquis, R. w., Ru, Y.,Vasko-Moser, J. A., Smith, B. R., Tomaszek, T. and Gowen, M. Potent andselective inhibition of human cathepsin K leads to inhibition of boneresorption in vivo in a nonhuman primate. J. Bone Miner. Res.,16:1739-1746;2001; and Votta, B. J., Levy, M. A., Badger, A., Dodds, R.A., James, I. E., Thompson, S., Bossard, M. J., Carr, T., Connor, J. R.,Tomaszek, T. A., Szewczuk, L., Drake, F. H., Veber, D., and Gowen, M.Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption bothin vivo and in vitro. J. Bone Miner. Res. 12:1396-1406; 1997.

Another embodiment of the invention is a method of treating orpreventing osteoporosis in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or any of the above pharmaceutical compositions describedabove. The utility of cathepsin K inhibitors in the treatment orprevention of osteoporosis is known in the literature, see Saftig, P.,Hunziker, E., Wehmeyer, O., Jones, S., Boyde, A., Rommerskirch, W.,Moritz, J. D., Schu, P., and Vonfigura, K. Impaired osteoclast boneresorption leads to osteoporosis in cathepsin K-deficient mice. Proc.Natl. acad. Sci. USA 95:13453-13458; 1998.

Another embodiment of the invention is a method treating cancer in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above. It is known in theliterature that Cathepsin K is expressed in human breast carcinoma, seeLittlewood-Evans A J, Bilbe G, Bowler W B, Farley D, Wlodarski B, KokuboT, Inaoka T, Sloane J, Evans D B, Gallagher J A, “Theosteoclast-associated protease cathepsin K is expressed in human breastcarcinoma.”Cancer Res Dec. 1, 1997; 57(23):5386-90.

Exemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of osteoporosis in a mammal in need thereof. Still furtherexemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of: bone loss, bone resorption, bone fractures, metastaticbone disease and/or disorders related to cathepsin functioning.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch, and lubricating agents, such asmagnesium stearate, are commonly added. For oral administration incapsule form, useful diluents include lactose and dried corn starch. Fororal use of a therapeutic compound according to this invention, theselected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. For oraladministration in the form of a tablet or capsule, the active drugcomponent can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, starch, sucrose, glucose,methyl cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, mannitol, sorbitol and the like; for oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like. When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

The compounds of the present invention can be used in combination withother agents useful for treating cathepsin-mediated conditions. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating cathepsin-mediated conditions includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to estrogen functioning.

The instant compounds are also useful in combination with known agentsuseful for treating or preventing osteoporosis, glucocorticoid inducedosteoporosis, Paget's disease, abnormally increased bone turnover,periodontal disease, tooth loss, bone fractures, rheumatoid arthritis,osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta,metastatic bone disease, hypercalcemia of malignancy, and multiplemyeloma. Combinations of the presently disclosed compounds with otheragents useful in treating or preventing osteoporosis or other bonedisorders are within the scope of the invention. A person of ordinaryskill in the art would be able to discern which combinations of agentswould be useful based on the particular characteristics of the drugs andthe disease involved. Such agents include the following: an organicbisphosphonate; an estrogen receptor modulator; an androgen receptormodulator; an inhibitor of osteoclast proton ATPase; an inhibitor ofHMG-CoA reductase; an integrin receptor antagonist; an osteoblastanabolic agent, such as PTH; and the pharmaceutically acceptable saltsand mixtures thereof. A preferred combination is a compound of thepresent invention and an organic bisphosphonate. Another preferredcombination is a compound of the present invention and an estrogenreceptor modulator. Another preferred combination is a compound of thepresent invention and an androgen receptor modulator. Another preferredcombination is a compound of the present invention and an osteoblastanabolic agent.

“Organic bisphosphonate” includes, but is not limited to, compounds ofthe chemical formula

wherein n is an integer from 0 to 7 and wherein A and X areindependently selected from the group consisting of H, OH, halogen, NH₂,SH, phenyl, C1-C30 alkyl, C3-C30 branched or cycloalkyl, bicyclic ringstructure containing two or three N, C1-C30 substituted alkyl, C1-C10alkyl substituted NH₂, C3-C10 branched or cycloalkyl substituted NH₂,C1-C10 dialkyl substituted NH₂, C1-C10 alkoxy, C1-C10 alkyl substitutedthio, thiophenyl, halophenylthio, C1-C10 alkyl substituted phenyl,pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, andbenzyl, such that both A and X are not selected from H or OH when n is0; or A and X are taken together with the carbon atom or atoms to whichthey are attached to form a C3-C10 ring.

In the foregoing chemical formula, the alkyl groups can be straight,branched, or cyclic, provided sufficient atoms are selected for thechemical formula. The C1-C30 substituted alkyl can include a widevariety of substituents, nonlimiting examples which include thoseselected from the group consisting of phenyl, pyridyl, furanyl,pyrrolidinyl, imidazonyl, NH₂, C1-C10 alkyl or dialkyl substituted NH₂,OH, SH, and C1-C10 alkoxy.

The foregoing chemical formula is also intended to encompass complexcarbocyclic, aromatic and hetero atom structures for the A and/or Xsubstituents, nonlimiting examples of which include naphthyl, quinolyl,isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives of the bisphosphonatesare also useful herein. Non-limiting examples of salts include thoseselected from the group consisting alkali metal, alkaline metal,ammonium, and mono-, di-, tri-, or tetra-C1-C30-alkyl-substitutedammonium. Preferred salts are those selected from the group consistingof sodium, potassium, calcium, magnesium, and ammonium salts. Morepreferred are sodium salts. Non-limiting examples of derivatives includethose selected from the group consisting of esters, hydrates, andamides.

It should be noted that the terms “bisphosphonate” and“bisphosphonates”, as used herein in referring to the therapeutic agentsof the present invention are meant to also encompass diphosphonates,biphosphonic acids, and diphosphonic acids, as well as salts andderivatives of these materials. The use of a specific nomenclature inreferring to the bisphosphonate or bisphosphonates is not meant to limitthe scope of the present invention, unless specifically indicated.Because of the mixed nomenclature currently in use by those of ordinaryskill in the art, reference to a specific weight or percentage of abisphosphonate compound in the present invention is on an acid activeweight basis, unless indicated otherwise herein. For example, the phrase“about 5 mg of a bone resorption inhibiting bisphosphonate selected fromthe group consisting of alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof, on an alendronic acid active weightbasis” means that the amount of the bisphosphonate compound selected iscalculated based on 5 mg of alendronic acid.

Non-limiting examples of bisphosphonates useful herein include thefollowing:

Alendronate, also known as Alendronic acid,4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, alendronate sodium,alendronate monosodium trihydrate or4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate

Alendronate is described in U.S. Pat. No. 4,922,007, to Kieczykowski etal., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski etal., issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer et al.,issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et al., issuedJul. 15, 1997, all of which are incorporated by reference herein intheir entirety.

Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175, Yamanouchi(incadronate, formerly known as cimadronate), as described in U.S. Pat.No. 4,970,335, to Isomura et al., issued Nov. 13, 1990, which isincorporated by reference herein in its entirety.

1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), and thedisodium salt (clodronate, Procter and Gamble), are described in BelgiumPatent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of whichare incorporated by reference herein in their entirety.

1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid(EB-1053).

1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,also known as BM-210955, Boehringer-Mannheim (ibandronate), is describedin U.S. Pat. No. 4,927,814, issued May 22, 1990, which is incorporatedby reference herein in its entirety.

1-hydroxy-2-imidazo-(1,2-a)pyridin-3-yethylidene (minodronate).

6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate).

3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid(olpadronate).

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate).

[2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate) isdescribed in U.S. Pat. No. 4,761,406, which is incorporated by referencein its entirety.

1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate), is described in U.S. Pat. No. 5,583,122, which isincorporated by reference in its entirety.

(4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate) asdescribed in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989,which is incorporated by reference herein in its entirety.

1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid(zoledronate).

Nonlimiting examples of bisphosphonates include alendronate,cimadronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, and zolendronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially a sodium, potassium, calcium,magnesium or ammonium salt of alendronic acid. Exemplifying thepreferred bisphosphonate is the sodium salt of alendronate, especially ahydrated sodium salt of alendronate. The salt can be hydrated with awhole number of moles of water or non whole numbers of moles of water.Further exemplifying the preferred bisphosphonate is a hydrated sodiumsalt of alendronate, especially when the hydrated salt is alendronatemonosodium trihydrate.

It is recognized that mixtures of two or more of the bisphosphonateactives can be utilized.

The precise dosage of the organic bisphosphonate will vary with thedosing schedule, the particular bisphosphonate chosen, the age, size,sex and condition of the mammal or human, the nature and severity of thedisorder to be treated, and other relevant medical and physical factors.Thus, a precise pharmaceutically effective amount cannot be specified inadvance and can be readily determined by the caregiver or clinician.Appropriate amounts can be determined by routine experimentation fromanimal models and human clinical studies. Generally, an appropriateamount of bisphosphonate is chosen to obtain a bone resorptioninhibiting effect, i.e. a bone resorption inhibiting amount of thebisphosphonate is administered. For humans, an effective oral dose ofbisphosphonate is typically from about 1.5 to about 6000 μg/kg bodyweight and preferably about 10 to about 2000 μg/kg of body weight. Foralendronate monosodium trihydrate, common human doses which areadministered are generally in the range of about 2 mg/day to about 40mg/day, preferably about 5 mg/day to about 40 mg/day. In the U.S.presently approved dosages for alendronate monosodium trihydrate are 5mg/day for preventing osteoporosis, 10 mg/day for treating osteoporosis,and 40 mg/day for treating Paget's disease.

In alternative dosing regimens, the bisphosphonate can be administeredat intervals other than daily, for example once-weekly dosing,twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In aonce weekly dosing regimen, alendronate monosodium trihydrate would beadministered at dosages of 35 mg/week or 70 mg/week.

“Estrogen receptor modulators” refers to compounds which interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, estrogen, progestogen, estradiol, droloxifene, raloxifene,lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

Non-steroidal compounds having androgen receptor modulating propertiesare disclosed in U.S. Pat. Nos. 5,688,808; 5,696,130; 6,017,924;6,093,821; WO 01/16139 (published 8 Mar. 2001); and WO 01/16108(published 8 Mar. 2001), all assigned to ligand Pharmaceuticals, and inWO 01/27086, assigned to Kaken Pharm. Co. Additional background for therationale behind the development of Selective Androgen ReceptorModulators is found in L. Zhi and E. Martinborough in Ann. Rep. Med.Chem. 36: 169-180 (2001). Non-steroidal SARMs were disclosed in J. P.Edwards, “New Nonsteroidal Androgen Receptor Modulators Based on4-(Trifluoromethyl)-2(1H)-Pyrrolidino[3,2-g]quinolinone,” Bioorg. Med.Chem. Lett., 8: 745-750 (1998) and in L. Zhi et al., “Switching AndrogenReceptor Antagonists to Agonists by Modifying C-ring Substituents onPiperidino[3,4-g]quinolinone,” Biorg. Med. Chem. Lett., 9: 1009-1012(1999).

“An inhibitor of osteoclast proton ATPase” refers to an inhibitor of theproton ATPase, which is found on the apical membrane of the osteoclast,and has been reported to play a significant role in the bone resorptionprocess. This proton pump represents an attractive target for the designof inhibitors of bone resorption which are potentially useful for thetreatment and prevention of osteoporosis and related metabolic diseases.See C. Farina et al., “Selective inhibitors of the osteoclast vacuolarproton ATPase as novel bone antiresorptive agents,” DDT, 4: 163-172(1999)), which is hereby incorporated by reference in its entirety.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos.4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S.Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165,4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatinLIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may preferably be formed from the open-acid, and allsuch forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically acceptablesalts” with respect to the HMG-CoA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl)aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

As used above, “integrin receptor antagonists” refers to compounds whichselectively antagonize, inhibit or counteract binding of a physiologicalligand to the α_(v)β₃ integrin, to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe αvβ5 integrin, to compounds which antagonize, inhibit or counteractbinding of a physiological ligand to both the α_(v)β₃ integrin and theα_(v)β₅ integrin, and to compounds which antagonize, inhibit orcounteract the activity of the particular integrin(s) expressed oncapillary endothelial cells. The term also refers to antagonists of theα_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The termalso refers to antagonists of any combination of α_(v)β₃, α_(v)β₅,α_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. H.N. Lodeand coworkers in PNAS USA 96: 1591-1596 (1999) have observed synergisticeffects between an antiangiogenic αv integrin antagonist and atumor-specific antibody-cytokine (interleukin-2) fusion protein in theeradication of spontaneous tumor metastases. Their results suggestedthis combination as having potential for the treatment of cancer andmetastatic tumor growth. α_(v)β₃ integrin receptor antagonists inhibitbone resorption through a new mechanism distinct from that of allcurrently available drugs. Integrins are heterodimeric transmembraneadhesion receptors that mediate cell-cell and cell-matrix interactions.The α and β integrin subunits interact non-covalently and bindextracellular matrix ligands in a divalent cation-dependent manner. Themost abundant integrin on osteoclasts is α_(v)β₃ (>10⁷/osteoclast),which appears to play a rate-limiting role in cytoskeletal organizationimportant for cell migration and polarization: The α_(v)β₃ antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of macular degeneration, inhibition of arthritis,and inhibition of cancer and metastatic growth. Nonlimiting examples ofintegrin receptor antagonists, and methods for their preparation, arefound in U.S. Pat. No. 5,925,655 (issued Jul. 20, 1999), U.S. Pat. No.6,211,184 (issued Apr. 3, 2001), U.S. Pat. No. 5,919,792 (issued Jul. 6,1999), U.S. Pat. No. 5,952,792 (issued Sep. 14, 1999), U.S. Pat. No.6,017,925 (issued Jan. 25, 2000), U.S. Pat. No. 6,048,861 (issued Apr.11, 2000), U.S. Pat. No. 6,232,308 (issued May 15, 2001), U.S. Pat. No.6,358,970 (issued Mar. 19, 2002), U.S. Pat. No. 6,040,311 (issued Mar.21, 2000), U.S. Pat. No. 6,066,648 (issued May 23, 2000), U.S. Pat. No.6,211,191 (issued Apr. 3, 2001), U.S. Pat. No. 6,017,926 (issued Jan.25, 2000), U.S. Pat. No. 6,090,944 (Jul. 18, 2000), U.S. Pat. No.6,410,526 (issued Jun. 25, 2002), U.S. Pat. No. 6,413,955 (issued Jul.2, 2002), U.S. Pat. No. 6,426,353 (issued Jul. 30, 2002), U.S. Pat. No.6,444,680 (issued Sep. 3, 2002), and in PCT International PublicationNumbers WO 00/48603 (published Aug. 24, 2000), WO 01/53297 (publishedJul. 26, 2001), WO 01/53262 (published Jul. 26, 2001), WO 02/22616(published Mar. 21, 2002), WO 02/07730 (published Jan. 31, 2002), WO02/28840 (published Apr. 11, 2002), WO 02/40505 (published May 23,2002).

“An osteoblast anabolic agent” refers to agents that build bone, such asPTH. The intermittent administration of parathyroid hormone (PTH) or itsamino-terminal fragments and analogues have been shown to prevent,arrest, partially reverse bone loss and stimulate bone formation inanimals and humans. For a discussion refer to D. W. Dempster et al.,“Anabolic actions of parathyroid hormone on bone,” Endocr Rev 14:690-709 (1993). Studies have demonstrated the clinical benefits ofparathyroid hormone in stimulating bone formation and thereby increasingbone mass and strength. Results were reported by R M Neer et al., in NewEng J Med 344 1434-1441 (2001).

In addition, parathyroid hormone-related protein fragments or analogues,such as PTHrP-(1-36) have demonstrated potent anticalciuric effects [seeM. A. Syed et al., “Parathyroid hormone-related protein-(1-36)stimulates renal tubular calcium reabsorption in normal humanvolunteers: implications for the pathogenesis of humoral hypercalcemiaof malignancy,” JCEM 86: 1525-1531 (2001)) and may also have potentialas anabolic agents for treating osteoporosis.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents. The present inventionincludes within its scope prodrugs of the compounds of this invention.In general, such prodrugs will be functional derivatives of thecompounds of this invention which are readily convertible in vivo intothe required compound. Thus, in the methods of treatment of the presentinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985, which is incorporated byreference herein in its entirety. Metabolites of these compounds includeactive species produced upon introduction of compounds of this inventioninto the biological milieu.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The terms “treating” or “treatment” of a disease as used hereinincludes: preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease; inhibiting the disease, i.e., arresting orreducing the development of the disease or its clinical symptoms; orrelieving the disease, i.e., causing regression of the disease or itsclinical symptoms.

The term “bone resorption,” as used herein, refers to the process bywhich osteoclasts degrade bone.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of osteoporosis or other bone disorders,comprising the administration of a therapeutically effective amount ofthe compounds of this invention, with or without pharmaceuticallyacceptable carriers or diluents. Suitable compositions of this inventioninclude aqueous solutions comprising compounds of this invention andpharmacologically acceptable carriers, e.g., saline, at a pH level,e.g., 7.4. The solutions may be introduced into a patient's bloodstreamby local bolus injection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for a cathepsin dependentcondition. Oral dosages of the present invention, when used for theindicated effects, will range between about 0.01 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably, from about 1 mg to about 100 mg of activeingredient. Intravenously, the most preferred doses will range fromabout 0.1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittant throughout the dosage regimen.

These and other aspects of the invention will be apparent from theteachings contained herein.

Definitions

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

When any variable (e.g. R¹, R², R^(a) etc.) occurs more than one time inany constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents indicate that theindicated bond may be attached to any of the substitutable ring carbonatoms. If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear, branched, or cyclic arrangement. For example,“C₁-C₁₀ alkyl” specifically includes methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on. “Alkoxy”represents an alkyl group of indicated number of carbon atoms attachedthrough an oxygen bridge.

The term “cycloalkyl” or “carbocycle” shall mean cyclic rings of alkanesof three to eight total carbon atoms, or any number within this range(i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight or branched, containingfrom 2 to 10 carbon atoms and at least 1 carbon to carbon double bond.Preferably 1 carbon to carbon double bond is present, and up to 4non-aromatic carbon-carbon double bonds may be present. Thus, “C₂-C₆alkenyl” means an alkenyl radical having from 2 to 6 carbon atoms.Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. Asdescribed above with respect to alkyl, the straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “cycloalkenyl” shall mean cyclic rings of 3 to 10 carbon atomsand at least 1 carbon to carbon double bond (i.e., cycloprenpyl,cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl orcycloocentyl).

The term “alkynyl” refers to a hydrocarbon radical straight or branched,containing from 2 to 10 carbon atoms and at least 1 carbon to carbontriple bond. Up to 3 carbon-carbon triple bonds may be present. Thus,“C₂-C₆ alkynyl” means an alkynyl radical having from 2 to 6 carbonatoms. Alkynyl groups include ethynyl, propynyl and butynyl. Asdescribed above with respect to alkyl, the straight, branched or cyclicportion of the alkynyl group may contain triple bonds and may besubstituted if a substituted alkyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 10 atoms in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl oracenaphthyl. In cases where the aryl substituent is bicyclic and onering is non-aromatic, it is understood that attachment is via thearomatic ring.

The term “heteroaryl”, as used herein, represents a stable monocyclic,bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein-atleast one ring is aromatic and contains from 1 to 4 heteroatoms selectedfrom the group consisting of O, N and S. Heteroaryl groups within thescope of this definition include but are not limited to:benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl,thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl,hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl,carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl,furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where theheteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Ifthe heteroaryl contains nitrogen atoms, it is understood that thecorresponding N-oxides thereof are also encompassed by this definition.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo. The term“keto” means carbonyl (C═O). The term “alkoxy” as used herein means analkyl portion, where alkyl is as defined above, connected to theremainder of the molecule via an oxygen atom. Examples of alkoxy includemethoxy, ethoxy and the like.

The term “haloalkyl” includes an alkyl portion, where alkyl is asdefined above, which is substituted with one to five halo.

The term “arylalkyl” includes an alkyl portion where alkyl is as definedabove and to include an aryl portion where aryl is as defined above.Examples of arylalkyl include, but are not limited to, benzyl,fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, and chlorophenylethyl. Examples of alkylaryl include,but are not limited to, toluyl, ethylphenyl, and propylphenyl.

The term “heteroarylalkyl” as used herein, shall refer to a system thatincludes a heteroaryl portion, where heteroaryl is as defined above, andcontains an alkyl portion. Examples of heteroarylalkyl include, but arenot limited to, thienylmethyl, thienylethyl, thienylpropyl,pyridylmethyl, pyridylethyl and imidazoylmethyl

The term “hydroxyalkyl” means a linear monovalent hydrocarbon raidcal ofone to six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with one or two hydroxy groups,provided that if two hydroxy groups are present they are not both on thesame carbon atom. Representative examples include, but are not limitedto, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, andthe like.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 10-membered nonaromatic ring containing from 1 to 4heteroatoms selected from the group consisting of O, N and S, andincludes bicyclic groups. “Heterocyclyl” therefore includes, but is notlimited to the following: imidazolyl, piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,dihydropiperidinyl, tetrahydrothiophenyl and the like. If theheterocycle contains a nitrogen, it is understood that the correspondingN-oxides thereof are also emcompassed by this definition.

The present invention also includes N-oxide derivatives and protectedderivatives of compounds of Formula I. For example, when compounds ofFormula I contain an oxidizable nitrogen atom, the nitrogen atom can beconverted to an N-oxide by methods well known in the art. Also whencompounds of Formula I contain groups such as hydroxy, carboxy, thiol orany group containing a nitrogen atom(s), these groups can be protectedwith a suitable protecting groups. A comprehensive list of suitableprotective groups can be found in T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, Inc. 1981, the disclosure of whichis incorporated herein by reference in its entirety. The protectedderivatives of compounds of Formula I can be prepared by methods wellknown in the art.

The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl substituents may be unsubstituted or unsubstituted, unlessspecifically defined otherwise. For example, a (C₁-C₆)alkyl may besubstituted with one or more substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl,piperidinyl, and so on. In the case of a disubstituted alkyl, forinstance, wherein the substituents are oxo and OH, the following areincluded in the definition: —(C═O)CH₂CH(OH)CH₃, —(C═O)OH,—CH₂(OH)CH₂CH(O), and so on.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., aryl C₀₋₈ alkyl) it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed inorganic or organic acids. For example,conventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like, as well as salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic and the like. The preparation of the pharmaceuticallyacceptable salts described above and other typical pharmaceuticallyacceptable salts is more fully described by Berg et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977:66:1-19, hereby incorporated by reference.The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic or acidic moiety by conventional chemical methods. Generally, thesalts of the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

For purposes of this specification, the following abbreviations have theindicated meanings:

-   BuLi=butyl lithium-   Bu₄NHSO₄=butyl aminosulfate-   CH₂Cl₂=methylene chloride-   CrO₃=chromium oxide-   DMAP=4-(dimethylamino)pyridine-   Et₃N=triethylamine-   EtOAc=ethyl acetate-   EtOH=ethanol-   H₅IO₆ =periodic acid-   LiOH=lithium hydroxide-   MeOH=methanol-   MgSO₄=magnesium sulfate-   NaCNBH₃=sodium cyanoborohydride-   Na₂CO₃=sodium carbonate-   NaClO=sodium hypochlorite-   NaHCO₃=sodium hydrogencarbonate-   NaHPO₄=sodium hydrogenphosphate-   NaHSO₃=sodium hydrogensulfite-   NaOH=sodium hydroxide-   Na₂WO₄.2H₂O=sodium tungstate dihydrate-   NH₄Cl=ammonium chloride-   Pd/C=palladium on carbon-   PdCl₂(dppf)=[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(OAc)₂=palladium acetate-   iPr₂EtN=diisopropylethylamine-   PyBOP=Benzotriazol-1-yl-oxytripyrrolidinophosphonium    hexafluorophosphate-   PG=protecting group-   PPh₃=triphenylphosphine-   rt=room temperature-   sat. aq.=saturated aqueous-   SiO₂=silicon dioxide-   THF=tetrahydrofuran-   TiCl₄=titanium chloride-   tlc=thin layer chromatography-   Me=methyl-   Et=ethyl

The novel compounds of the present invention can be prepared accordingto the following general procedures using appropriate materials and arefurther exemplified by the following specific examples. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The followingexamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can be used to prepare these compounds.All temperatures are degrees Celsius unless otherwise noted.

Schemes

Compounds of the present invention can be prepared according to Scheme1, as indicated below. Thus an α-amino ester may be added to a haloalkylketone to form an aminal which may be dehydrated to an imine in thepresence of a dehydrating agent such as TiCl₄, MgSO₄ or isopropyltrifluoroacetate. Reduction of the imine with a reducing agent such assodium cyanoborohydride or sodium borohydride provides the amine. Apalladium-catalyzed Suzuki coupling with an appropriate boronic acidprovides the left hand side of the molecule. Ester hydrolysis andcoupling with the seven-membered ring amine (synthesis in J. Med. Chem.44 1380, 2001) provides the amide. This molecule is elaborated tocompounds of the present invention by removal of the amine protectinggroup, coupling with an aryl/heteroarylSO₂Cl or aryl/heteroarylC(O)Cland oxidation of the alcohol to the ketone.

Compounds of the present invention may also be prepared according toScheme 2, as indicated below. A haloalkylketone or aldehyde may becondensed with an amino alcohol to give a cyclic aminal. Treatment with3 equivalents of a Grignard reagent or organolithium reagent willprovide the appropriate alkylated amino alcohol. Oxidation of thealcohol with a chromium system such as H₅IO₆/CrO₃, or alternatively by atwo-step oxidation (eg oxalyl chloride/DMSO/Et₃N followed by NaClO) willprovide the corresponding carboxylic acid. This acid may be converted tocompounds of the current invention as described in Scheme 1.

Compounds of the current invention may also be prepared according toScheme 3, as indicated below. A hemiacetal may be condensed with anamino alcohol in which the alcohol moiety is protected with a suitableprotecting group. Treatment of the resulting imine with a Grignardreagent or organolithium reagent and removal of the alcohol protectinggroup will provide the appropriate alkylated amino alcohol. Apalladium-catalyzed Suzuki coupling with an appropriate boronic acid andoxidation of the alcohol with H₅IO₆/CrO₃ will provide the correspondingcarboxylic acid. This acid may be converted to compounds of the currentinvention as described in Scheme 1.

Pharmaceutical Composition

As a specific embodiment of this invention, 100 mg ofN¹-(cyanomethyl)-N²-[2,2,2-trifluoro-1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethyl]-L-leucinamide,is formulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

The compounds disclosed in the present application exhibited activity inthe following assays.

Cathepsin K Assay

Serial dilutions (1/3) from 500 μM down to 0.0085 μM of test compoundswere prepared in dimethyl sulfoxide (DMSO). Then 2 μL of DMSO from eachdilution were added to 50 μL of assay buffer (MES, 50 mM (pH 5.5); EDTA,2.5 mM; and DTT, 2.5 mM) and 25 μL of human cathepsin K (0.1 nM) inassay buffer solution. The assay solutions were mixed for 5-10 secondson a shaker plate and incubated for 15 minutes at room temperature.Z-Leu-Arg-AMC (8 μM) in 25 μL of assay buffer was added to the assaysolutions. Hydrolysis of the coumarin leaving group (AMC) was followedby spectrofluorometry (Exλ=355 nm; Emλ=460 nm) for 10 minutes. Percentof inhibition were calculated by fitting experimental values to standardmathematical model for dose response curve.

Cathepsin L Assay

Serial dilutions (1/3) from 500 μM down to 0.0085 μM of test compoundswere prepared in dimethyl sulfoxide (DMSO). Then 2 μL of DMSO from eachdilution were added to 50 μL of assay buffer (MES, 50 mM (pH 5.5); EDTA,2.5 mM; and DTT, 2.5 mM) and 25 μL of human cathepsin L (1.5 nM) inassay buffer solution. The assay solutions were mixed for 5-10 secondson a shaker plate and incubated for 15 minutes at room temperature.Z-Leu-Arg-AMC (8 μM) in 25 μL of assay buffer was added to the assaysolutions. Hydrolysis of the coumarin leaving group (AMC) was followedby spectrofluorometry (Exλ=355 nm; Emλ=460 nm) for 10 minutes. Percentof inhibition were calculated by fitting experimental values to standardmathematical model for dose response curve.

Cathepsin B Assay

Serial dilutions (1/3) from 500 μM down to 0.0085 μM of test compoundswere prepared in dimethyl sulfoxide (DMSO). Then 2 μL of DMSO from eachdilution were added to 50 μL of assay buffer (MES, 50 mM (pH 5.5); EDTA,2.5 mM; and DTT, 2.5 mM) and 25 μL of human cathepsin B (2.5 nM) inassay buffer solution. The assay solutions were mixed for 5-10 secondson a shaker plate and incubated for 15 minutes at room temperature.Z-Leu-Arg-AMC (8 μM) in 25 μL of assay buffer was added to the assaysolutions. Hydrolysis of the coumarin leaving group (AMC) was followedby spectrofluorometry (Exλ=355 nm; Emλ=460 nm) for 10 minutes. Percentof inhibition were calculated by fitting experimental values to standardmathematical model for dose response curve.

Cathepsin S Assay

Serial dilutions (1/3) from 500 μM down to 0.0085 μM of test compoundswere prepared in dimethyl sulfoxide (DMSO). Then 2 μL of DMSO from eachdilution were added to 50 μL of assay buffer (MES, 50 mM (pH 5.5); EDTA,2.5 mM; and DTT, 2.5 mM) and 25 μL of human cathepsin S (4 nM) in assaybuffer solution. The assay solutions were mixed for 5-10 seconds on ashaker plate and incubated for 15 minutes at room temperature.Z-Leu-Arg-AMC (8 μM) in 25 μL of assay buffer was added to the assaysolutions. Hydrolysis of the coumarin leaving group (AMC) was followedby spectrofluorometry (Exλ=355 nm; Emλ=460 nm) for 10 minutes. Percentof inhibition were calculated by fitting experimental values to standardmathematical model for dose response curve.

EXAMPLE 1 SYNTHESIS OFN¹-[3-OXO-1-(PYRIDIN-2-YLSULFONYL)AZEPAN-4-YL]-N²-{(1S)-2,2,2-TRIFLUORO-1-[4′-(METHYLSULFONYL)-1,1′-BIPHENYL-4-YL]ETHYL}-L-LEUCINAMIDE

Step 1: Preparation of(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine

To a room temperature dichloromethane (100 mL) solution of L-leucinol(6.0 g) was added triethylamine (11 mL), DMAP (0.1 g) andt-butyldimethylsilyl chloride (8.5 g). The mixture was stirred at roomtemperature for 2 hours and then water was added. The organic layer wasseparated and the aqueous further extracted with dichloromethane. Thecombined organic layers were washed with brine, dried with magnesiumsulfate and the solvent was removed in vacuo to yield the titlecompound, a residue which was used as such in the next reaction. ¹H NMR(CD₃COCD₃) δ 3.48(m, 2H), 3.32(m, 1H), 2.76(m, 1H), 1.78(m, 1H),1.22-1.02(m, 2H), 0.88(m, 15H), 0.06(s, 6H).

Step 2: Preparation of(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine

A toluene (300 mL) solution of(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine from Step1 (50 g) and tifluoroacetaldehyde methyl hemiacetal (35 mL) was heatedto reflux for 16 hours during which time water was collected in aDean-Stark trap. The solvent was evaporated in vacuum and the residuewas purified on SiO₂ using hexanes and ethyl acetate (9:1) as eluant toyield the title compound. ¹H NMR (CD₃COCD₃) δ 7.88(m, 1H), 3.76-3.45(m,3H), 1.60-1.25(m, 3H), 0.88(m, 15H), 0.06(s, 3H), 0.04(s, 3H).

Step 3: Preparation of(2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]amino}-4-methylpentan-1-ol

n-Buli (2.5 M in hexanes, 42 mL) was added to a −70° C. THF (400 mL)solution of 1,4-dibromobenzene (25.8 g) and the mixture was stirred for25 minutes. A THF (30 mL) solution of(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine(31 g) was then added dropwise and the mixture was stirred for 1.5hours. It was then poured slowly into a mixture of ethyl acetate (500mL), water (2 L), ice (300 g) and ammonium chloride (100 g) undervigorous stirring. The organic layer was separated and the aqueousfurther extracted with ethyl acetate (2×500 mL). The combined organiclayers were washed with brine, dried with magnesium sulfate and thesolvent was removed in vacuo to yield a residue, which was used as such.The residue from above was dissolved in THF (250 ml) and the solutionwas cooled to 0° C. A 1 M THF solution of t-butylammonium fluoride (110mL) was added dropwise and the mixture was reacted for 4 hours. It waspoured into ethyl acetate (300 mL), water (2 L) and ammonium chloride(100 g) under vigorous stirring. The organic layer was separated and theaqueous further extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine, dried with magnesium sulfate andthe solvent was removed in vacuo to yield a residue which was purifiedpurified on SiO₂ using a gradient of ethyl acetate and hexanes (1:5 to1:4) as eluant to yield the title compound. ¹H NMR (CD₃COCD₃) δ 7.6(2H,d), 7.45(2H, d), 4.55(1H, m), 3.65-3.7(1H, m), 3.5-3.55(1H, m),3.25-3.35(1H, m), 2.6-2.7(1H, m), 2.25-2.35(1H, m), 1.65-1.75(1H, m),1.3-1.4(1H, m), 1.2-1.3(1H, m), 0.75-0.9(6H, dd).

Step 4: Preparation of(2S)-4methyl-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylthio)-1,1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol

A stream of nitrogen was passed through a suspension made of the bromidefrom Step 3 (27.7 g), 4-(methylthio)phenylboronic acid (15.7 g), 2 MNa₂CO₃ (100 mL) and n-propanol (500 mL) for 15 minutes. A 1:3 mixture(3.5 g) of Pd(OAc)₂ and PPh₃ was then added and the reaction was warmedto 70° C. and stirred under nitrogen for 8 hours. The mixture was cooledto room temperature, diluted with ethylacetate (500 mL) and poured overwater (2 L) and ice (500 g). The ethyl acetate layer was separated andthe aqueous further extracted with ethyl acetate (200 mL). The combinedethyl acetate extracts were washed with 0.5 N NaOH (2×200 mL), aqueousNH₄Cl, brine and dried with magnesium sulfate. Removal of the solventleft a residue that was purified by chromatography on SiO₂ using agradient of ethyl acetate and hexanes (1:4 to 1:3) and again withacetone and toluene (1:10). The residue was dissolved in hot hexanes(200 mL) and the solution was allowed to cool to 0° C. under stirring.The obtained solid was filtered and dried to yield the title compound.¹H NMR (CD₃COCD₃) δ 7.7(2H, d), 7.65(2H, d), 7.6(2H, d), 7.35(2H, d),4.5-4.6(1H, m), 3.7(1H(OH), m), 3.5-3.6(1H, m), 3.3-3.4(1H, m), 2.7(1H,m), 2.5(3H, s), 2.3-2.4(1H(NH), m), 1.65-1.75(1H, m), 1.2-1.4(3H, m),0.8-0.9(6H, dd).

Step 5: Preparation of(2S)-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1.1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol

To a 0° C. solution of the sulfide (19 g) from Step 4 in toluene (400mL) was added Na₂WO₄.2H₂O (0.16 g) and Bu₄NHSO₄ (0.81 g). Then 30%hydrogen peroxide (12.2 mL) was slowly added and the mixture was stirredat room temperature for 4.5 hours. The mixture was poured slowly on amixture of ice, dilute aqueous sodium thiosulfate and ethyl acetate. Theorganic layer was separated and the aqueous further extracted with ethylacetate (2×100 mL). The combined organic layers were washed with brine,dried with magnesium sulfate and the solvent were removed in vacuo toyield a residue which was purified purified on SiO₂ using ethyl acetateand hexanes (1:1) as eluant to yield the product. ¹H NMR (CD₃COCD₃) δ8.05(2H, d), 8.0(2H, d), 7.85(2H, d), 7.7(2H, d), 4.6-4.7(1H, m),3.75(1H, m), 3.6(1H, m), 3.35-3.45(1H, m), 3.2(3H, s), 2.7-2.8(1H, m),2.35-2.45(1H, m), 1.7-1.8(1H, m), 1.2-1.5(2H, m), 0.8-0.95(6H, dd).

Step 6: Preparation ofN-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucine

A suspension of H₅IO₆/CrO₃ (529 mL of 0.44 M in CH3CN; see Note below)was cooled to 0° C. and a solution of the alcohol from Step 5 (20 g) inCH₃CN (230 mL) was added dropwise. The mixture was stirred at 0-5° C.for 3.5 hours. It was poured into pH 4 Na₂HPO₄ (1.5 L) under vigorousstirring and the mixture was extracted with diethyl ether (3×250 mL).The combined ether extracts were washed with water and brine (1:1),dilute aqueous NaHSO₃ and brine. The organic extract was dried withsodium sulfate, filtered and the solvents were evaporated to dryness toyield a residue that was split into two batches for the followingpurification.

The crude acid from above (10 g) was dissolved in isopropyl acetate (250mL) and extracted into cold 0.1 N NaOH (3×250 mL). The combined extractswere washed with diethyl ether (250 mL) and then slowly acidified with 6N HCl to pH 4. The carboxylic acid was extracted with isopropyl acetate(2×250 mL) and the isopropyl acetate layer dried and concentrated toyield the title compound essentially pure and used as such in the nextstep. Note. The oxidizing reagent (H₅IO₆/CrO₃) was prepared as describedin Tetrahedron Letters 39 (1998) 5323-5326 but using HPLC grade CH₃CN(contains 0.5% water); no water was added. ¹H NMR (CD₃COCD₃) δ 8.05(2H,d), 7.95(2H, d), 7.8(2H, d), 7.65(2H, d), 4.45-4.55(1H, m), 3.55-3.6(1H,m), 3.2(3H, s), 2.8-3.0(broad m, NH/OH)1.95-2.05(1H, m), 1.55-1.6(2H,m), 0.9-1.0(6H, m).

Step 7: Preparation of benzyl3-hydroxy-4-[(N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucyl)amino]azepane-1-carboxylate

To a cold (0° C.), stirred solution ofN-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucine(605 mg, 1.37 mmol) and benzyl 4-amino-3-hydroxyazepane-1-carboxylate(326 mg, 1.23 mmol, prepared according to J. Med. Chem. 44, 1380, 2001)in DMF (10 mL) was added Et₃N (0.45 mL, 3.22 mmol). The reaction mixturewas stirred for 1 h at 0° C. followed by 1 h at rt. Saturated aqueousNaHCO₃, 1 N NaOH and ether were added. The organic layer was washed withpH 3.5 phosphate buffer, dried over MgSO₄ and concentrated under reducedpressure. The residue obtained was purified by flash chromatography(gradient elution: 65% EtOAc in hexane to 100% EtOAc) to afford thetitle compound as a mixture of isomers.

Step 8: Preparation ofN¹-(3-hydroxyazepan-4-yl)-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide

A stirred solution of benzyl3-hydroxy4-[(N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucyl)amino]azepane-1-carboxylate(710 mg, 1.03 mmol) in a 2:1 mixture of EtOH/EtOAc (80 mL) was flushedwith H₂ and stirred at rt for 2 h. The suspension was filtered throughcelite and the filtrate was concentrated under reduced pressure toafford the title compound which was used as such in the next reaction.

Step 9: Preparation ofN¹-[3-hydroxy-1-(pyridin-2-ylsulfonyl)azepan-4-yl]-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide

To a cold (0° C.), stirred solution ofN¹-(3-hydroxyazepan-4-yl)-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide(567 mg, 1.02 mmol) in Et₃N (0.25 mL, 1.8 mmol) was addedpyridine-2-sulfonyl chloride (204 mg, 1.15 mmol). The reaction mixturewas warmed to rt and stirred for 1 h. The reaction was then transferredto a 4° C. fridge and left overnight. The mixture was partitionedbetween CH₂Cl₂ and saturated aqueous NaHCO₃. The organic layer waswashed with brine, filtered through cotton and concentrated underreduced pressure. The residue was purified by flash chromatography(gradient elution: 70% EtOAc in hexane to 100% EtOAc) to afford thetitle compound.

Step 10: Preparation ofN¹-[3-oxo-1-(pyridin-2-ylsulfonyl)azepan-4-yl]-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide

To a solution ofN¹-[3-hydroxy-1-(pyridin-2-ylsulfonyl)azepan-4-yl]-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide(460 mg, 0.73 mmol) in CH₂Cl₂ (15 mL) was added Dess Martin periodinane(420 mg, 0.99 mmol). The reaction was stirred at rt for 1 h and thendiluted with CH₂Cl₂. The solution was washed with 1 N NaOH and brine,filtered through cotton and concentrated under reduced pressure. Theresidue was purified by flash chromatography (gradient elution: 60%EtOAc in hexane to 100% EtOAc) to yield the title compound.

MS (+ESI): 695.3 [M+1)⁺

1. A compound of the formula:

wherein R¹ is hydrogen, C₁₋₆ alkyl, —SO₂R⁹, —C(O)R⁹ or arylC₁₋₆alkyl; R²is hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; R³ is hydrogen, C₁₋₆ alkylor C₂₋₆ alkenyl wherein said alkyl and alkenyl groups are optionallysubstituted with C₃₋₆ cycloalkyl or halo; R⁴ is hydrogen, C₁₋₆ alkyl orC₂₋₆ alkenyl wherein said alkyl and alkenyl groups are optionallysubstituted with C₃₋₆ cycloalkyl or halo; or R³ and R⁴ can be takentogether with the carbon atom to which they are attached to form a C₃₋₈cycloalkyl ring, C₅₋₈ cycloalkenyl ring, or five to seven memberedheterocyclyl wherein said cycloalkyl, cycloalkenyl and heterocyclylgroups are optionally substituted with C₁₋₆ alkyl, halo, hydroxyalkyl,hydroxy, alkoxy or keto; R⁵ is selected from hydrogen or C₁₋₆ allylsubstituted with 1-6 halo; R⁶ is aryl, heteroaryl, C₁₋₆ haloalkyl,arylalkyl or heteroarylalkyl, wherein said aryl, heteroaryl, arylalkyland heteroarylalkyl groups are optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, —SR⁹, —SR¹², —SOR⁹, —SOR¹²,—SO₂R⁹, —SO₂R¹², —SO₂CH(R¹²)(R¹¹), —OR¹², —N(R¹⁰)(R¹¹) or cyano; D isC₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkenyl, aryl, heteroaryl, C₃₋₈cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl andheterocyclyl groups, which may be monocyclic or bicyclic, are optionallysubstituted on either the carbon or the heteroatom with one to fivesubstituents selected from C₁₋₆ alkyl, halo or keto; R⁷ is hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkyloxy, halo, nitro, cyanheteroaryl, C₃₋₈ cycloalkyl, heterocyclyl, —C(O)OR¹⁰,—C(O)OSi[CH(CH₃)₂]₃, —OR¹⁰, —C(O)R¹⁰, —R¹⁰C(O)R⁹, —C(O)R⁹,—C(O)N(R¹²)(R¹²), —C(O)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —SR¹², —SR⁹,—R¹⁰SR⁹, —R⁹, —C(R⁹)₃, —C(R¹⁰)(R¹¹)N(R⁹)₂, —NR¹⁰C(O)NR¹⁰S(O)₂R⁹,—SO₂R¹², —SO(R¹²), —SO₂R⁹, —SO₂N(R^(c))(R^(d)), —SO₂CH(R¹⁰)(R¹¹),—SO₂N(R¹⁰)C(O)(R¹²), —SO₂(R¹⁰)C(O)N(R¹²)₂, —OSO₂R¹⁰, —N(R¹⁰)(R¹¹),—N(R¹⁰)C(O)N(R¹⁰)(R⁹), —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)SO₂(R¹⁰),—C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R⁹, —C(R¹⁰)(R¹¹)N(R¹⁰)R⁹,—C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)R⁹, R¹⁰S—,—C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b))₂, —C(R^(a))(R^(b))N(R^(a))(R^(b)),—C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)),—C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R⁹,—C(O)C(R^(a))(R^(b))S(R^(a))(R^(b)) orC(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said groups are optionallysubstituted on either the carbon or the heteroatom with one to fivesubstituents independently selected from C₁₋₆ alkyl, halo, keto, cyano,haloalkyl, hydroxyalkyl, —OR⁹, —O(aryl), —NO₂, —NH₂, —NHS(O)₂R⁸,—R⁹SO₂R¹², SO₂R¹², SO(R¹²), SO₂N(R^(c))(R^(d)), SO₂N(R¹⁰)C(O)(R¹²),—C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R10)(R¹¹)OH, —COOH,—C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹), —NH(CH₂)₂OH,—NHC(O)OR¹⁰, Si(CH₃)₃, heterocycyl, aryl or heteroaryl; R⁸ is hydrogenor C₁₋₆ alkyl; or R⁴ and R⁸ or can be taken together with any of theatoms to which they may be attached or are between them to form a 4-10membered heterocyclyl ring system wherein said ring system, which may bemonocyclic or bicyclic, is optionally substituted with C₁₋₆ alkyl, halo,hydroxyalkyl, hydroxy, keto, OR¹⁰, SR¹⁰ or N(R¹⁰)₂; R⁹ is selected fromthe group consisting of hydrogen, aryl, aryl(C₁₋₄) alkyl, heteroaryl,heteroaryl(C₁₋₄)alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl(C₁₋₄)alkyl, andheterocyclyl(C₁₋₄)alkyl wherein said groups can be optionallysubstituted with halo or alkoxy; R¹⁰ is hydrogen or C₁₋₆ alkyl R¹¹ ishydrogen or C₁₋₆ alkyl; R¹² is hydrogen or C₁₋₆ alkyl which isoptionally substituted with halo, alkoxy, cyano, —NR¹⁰ or —SR¹⁰; R^(a)is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆ alkyl)hydroxyl, —O(C₁₋₆alkyl), hydroxyl, halo, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl,wherein said alkyl, aryl, heteroaryl, C₃₋₈ cycloalkyl and heterocyclylcan be optionally substituted on either the carbon or the heteroatomwith C₁₋₆ alkyl or halo; R^(b) is hydrogen, C₁₋₆ alkyl, (C₁₋₆alkyl)aryl, (C₁₋₆ alkyl)hydroxyl, alkoxyl, hydroxyl, halo, aryl,heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl, wherein said alkyl, aryl,heteroaryl, C₃₋₈ cycloalkyl and heterocyclyl can be optionallysubstituted on either the carbon or the heteroatom with C₁₋₆ alkyl orhalo; or R^(a) and R^(b) can be taken together with the carbon atom towhich they are attached or are between them to form a C₃₋₈ cycloalkylring or C₃₋₈ heterocyclyl ring wherein said 3-8 membered ring system maybe optionally substituted with C₁₋₆ alkyl and halo; R^(c) is hydrogen orC₁₋₆ alkyl which is optionally substituted with halo or OR⁹; R^(d) ishydrogen or C₁₋₆ alkyl which is optionally substituted with halo or OR⁹;or R^(c) and R^(d) can be taken together with the nitrogen atom to whichthey are attached or are between them to form a C₃₋₈ heterocyclyl ringwhich is optionally substituted with C₁₋₆ alkyl, halo hydroxyalkyl,hydroxy, alkoxy or keto; n is independently selected from an integerfrom zero to three; and the pharmaceutically acceptable salts,stereoisomers and N-oxide derivatives thereof.
 2. The compound of claim2 wherein R³ and R⁴ are each independently selected from hydrogen orC₁₋₄ alkyl; or R³ and R⁴ can be taken together with the carbon atom towhich they are attached to form a six membered cycloalkyl ring system,and the pharmaceutically acceptable salts, stereoisomers and N-oxidederivatives thereof.
 3. The compound of claim 1 wherein R⁵ is C₁₋₆alkylsubstituted with 1-6 halo and R⁶ is C₁₋₆ alkyl substituted with 1-6halo; and the pharmaceutically acceptable salts, stereoisomers andN-oxide derivatives thereof.
 4. The compound of claim 1 wherein R⁵ ishydrogen and R⁶ is C₁₋₆ alkyl substituted with 1-6 halo; and thepharmaceutically acceptable salts, stereoisomers and N-oxide derivativesthereof.
 5. The compound of claim 1 wherein R⁵ is hydrogen and R⁶ isaryl or heteroaryl wherein said aryl or heteroaryl are optionallysubstituted with halo or —SO₂R¹²; and the pharmaceutically acceptablesalts, stereoisomers and N-oxide derivatives thereof.
 6. The compound ofclaim 1 wherein R⁴ and R⁸ or can be taken together with any of the atomsto which they may be attached or are between them to form a 4-10membered heterocyclyl ring system wherein said ring system, which may bemonocyclic or bicyclic, is optionally substituted with C₁₋₆ alkyl, halo,hydroxyalkyl, hydroxy, keto, —OR¹⁰, —SR¹⁰ or —N(R¹⁰)₂; and thepharmaceutically acceptable salts, stereoisomers and N-oxide derivativesthereof.
 7. The compound of claim 6 wherein R⁴ and R⁸ can be takentogether with any of the atoms to which they may be attached or arebetween them to form a 5 or 6 membered heterocyclyl ring system whereinsaid ring system, is optionally substituted with C₁₋₆ alkyl, halo,hydroxyalkyl, hydroxy, keto, —OR¹⁰, —SR¹⁰ or —N(R¹⁰)₂; and thepharmaceutically acceptable salts, stereoisomers and N-oxide derivativesthereof.
 8. The compound of claim 1 selected from:N¹-[3-Oxo-1-(pyridin-2-ylsulfonyl)azepan-4-yl]-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide,and the pharmaceutically acceptable salts, stereoisomers and N-oxidederivatives thereof.
 9. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.10. A pharmaceutical composition made by combining a compound accordingto any one of claims 1 to 8 and a pharmaceutically acceptable carrier.11. A process for making a pharmaceutical composition comprisingcombining a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 12. A method of inhibiting cathepsin activity in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of a compound according to claim
 1. 13.The method according to claim 13 wherein the cathepsin activity isCathepsin K activity.
 14. A method of treating of preventing a diseaseselected from: osteoporosis, glucocorticoid induced osteoporosis,Paget's disease, abnormally increased bone turnover, periodontaldisease, tooth loss, bone fractures, rheumatoid arthritis,osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta,metastatic bone disease, hypercalcemia of malignancy or multiple myelomain a mammal in need thereof by administering to the mammal atherapeutically effective amount of a compound according to claim
 1. 15.A method of treating or preventing bone loss in a mammal in need thereofby administering to the mammal a therapeutically effective amount of acompound according to claim
 1. 16. A method of treating or preventingosteoporosis in a mammal in need thereof by administering to the mammala therapeutically effective amount of a compound according to claim 1.17. A method of treating cathepsin dependent conditions in a mammal inneed thereof by administering to the mammal a therapeutically effectiveamount of a compound according to claim
 1. 18. A pharmaceuticalcomposition comprising a compound of claim 1 and another agent selectedfrom: an organic bisphosphonate, an estrogen receptor modulator, anandrogen receptor modulator, an inhibitor of osteoclast proton ATPase,an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, oran osteoblast anabolic agent, and the pharmaceutically acceptable saltsand mixtures thereof.
 19. A method of treating osteoporosis comprising acompound of claim 1 and another agent selected from: an organicbisphosphonate, an estrogen receptor modulator, an androgen receptormodulator, an inhibitor of osteoclast proton ATPase, an inhibitor ofHMG-CoA reductase, an integrin receptor antagonist, or an osteoblastanabolic agent, and the pharmaceutically acceptable salts and mixturesthereof.
 20. A method of treating bone loss comprising a compound ofclaim 1 and another agent selected from: an organic bisphosphonate, anestrogen receptor modulator, an androgen receptor modulator, aninhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoAreductase, an integrin receptor antagonist, or an osteoblast anabolicagent, and the pharmaceutically acceptable salts and mixtures thereof.21. A pharmaceutical composition comprising a compound of claim 1 andanother agent selected from: an organic bisphosphonate, an estrogenreceptor modulator, an androgen receptor modulator, an inhibitor ofosteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrinreceptor antagonist, or an osteoblast anabolic agent, and thepharmaceutically acceptable salts and mixtures thereof.
 22. A compoundof any one of claims 1 to 8, or a pharmaceutically acceptable salt,stereoisomer or N-oxide derivative thereof, for use in inhibitingcathepsin activity, such as cathepsin K activity.
 23. Use of a compoundof any one of claims 1 to 8, or a pharmaceutically acceptable salt,stereoisomer or N-oxide derivative thereof, in the manufacture of amedicament for treating or preventing a disease set forth in claim 14.